Acute limb compartment syndrome (CS), a potentially devastating complication of musculoskeletal trauma, is characterized by an increase in pressure within a closed osseofascial compartment, resulting in muscle-threatening and ultimately limb-threatening ischemia. [1-6] The fascia, unlike other body tissues, are unable to expand Fasciotomy, to fully decompress all the muscles in the involved compartments, remains the only effective treatment and current gold-standard surgical therapy. Despite a large body of literature dedicated to understanding the pathophysiology of CS, the mechanisms of CS-induced tissue damage are rather poorly understood.
Extremity CS occurs once swelling within a muscle compartment develops to such a degree that the tissue perfusion becomes compromised. The established view of the pathophysiological process of CS development is that increasing compartmental pressure compromises microcirculatory perfusion, thus restricting oxygen and nutrient delivery to vital tissues, ultimately resulting in cellular anoxia and severe tissue necrosis. [3,5,7,8] Unlike complete ischemia, CS causes myonecrosis in the face of patent vessels.
Surgery is needed immediately. A delay in relieving the mounting pressure within the fascia (measured sometimes in a delay as short as a few hours) will result in a permanent damage to delicate structures such as nerves and muscles and extensive propagation of tissues necrosis. Slowing of nerve conduction may occur after 2 hours of compression, neuropraxia after 3 to 4 hours, variable muscle tissue damage after 6 hours, and irreversible muscle tissue changes and irreversible changes to the nerves may include after 8 hours of tissue compression. In more severe cases, amputation may be required.
There is probably no way to prevent this condition. However, with prompt diagnosis and treatment, the prognosis is excellent for recovery of the muscles and nerves inside the compartment.
In view of the foregoing, the current surgical gold standard in CS diagnosis dictates that surgical fasciotomy must be performed within 6 hours to avoid permanent tissue damage.
Carbon monoxide (CO) gas is poisonous in high concentrations. However, it is now recognized that inhalation of low levels of carbon monoxide have anti-inflammatory effects in some models and to offer protection to microvascular perfusion. [12-16] Although the exogenous administration of CO via inhalation (250 ppm) has been shown beneficial during systemic inflammatory response syndrome [12,13], such method of administration results in increased carboxyhemoglobin (COHb) levels, thus presenting a potential threat to the host.
Carbon monoxide has been disclosed in U.S. Pat. No. 7,678,390 as a biomarker and therapeutic agent of heart, lung, liver, spleen, brain, skin and kidney diseases and other conditions and disease states including, for example, asthma, emphysema, bronchitis, adult respiratory distress syndrome, sepsis, cystic fibrosis, pneumonia, interstitial lung diseases, idiopathic pulmonary diseases, other lung diseases including primary pulmonary hypertension, secondary pulmonary hypertension, cancers, including lung, larynx and throat cancer, arthritis, wound healing, Parkinson's disease, Alzheimer's disease, peripheral vascular disease and pulmonary vascular thrombotic diseases such as pulmonary embolism. U.S. Pat. No. 7,687,079 discloses CO in the treatment of ileus. However, CO has never been suggested for the treatment of CS.
Transitional metal carbonyls, CO-releasing molecules (CO-RMs) have been used to deliver CO in a controlled manner without significantly altering COHb. [18, 19, 23] The major advantage of using CO-RMs versus inhaled CO is the ability to control CO delivery without significantly increasing COHb, and choice of various routes (intravenous, intraperitoneal, subcutaneous or tissue superfusion) of CO administration to target specific organs/tissues. Consequently, CO-RMs have received an increased attention for the potential pharmaceutical application. [17-19] CO-RMs have been shown to act pharmacologically in rat aortic and cardiac tissue, where liberation of CO produced vasorelaxant effects, decreased myocardial ischemia/reperfusion damage, and reduced inflammatory response in LPS-stimulated macrophages. [20-23]
U.S. Pat. No. 8,697,747 discloses the use of CORM for controlling bleeding (e.g., enhancing coagulation and reducing fibrinolysis). This patent, however, does not disclose, teach or suggest the use of CORM in the treatment, prevention or prophylaxis of CS. Furthermore, this patent shows that both inactive and active forms of CORM-2 enhanced coagulation and reduced fibrinolysis (see Examples 1 and 2), indicating that it is the CORM molecule itself the principal active agent and not the CO. Clotting cascade is not relevant to the topic of compartment syndrome.
In view of the foregoing there is a need to decrease the morbidity associated with CS and expand the surgical window by preserving the muscle tissue and its function.
An object of the present invention is to develop a method of treating CS, which would reduce the morbidity and disability in patients.